docirbrutinib (AS-1763) / Carna Biosci, BioNova Pharma - LARVOL DELTA

Docirbrutinib (AS-1763), a novel non-COVALENT BTK inhibitor, demonstrates efficacy in BTK inhibitor-resistant mutant cells (ASH 2025) - "Overexpression of the L528W mutant in OCI-Ly10 cells conferred resistance to both ibrutiniband pirtobrutinib; however, docirbrutinib retained its antiproliferative activity in these cells. Docirbrutinib is a novel ncBTKi characterized by a slow off-rate that enables sustained BTK inhibition,potentially leading to prolonged therapeutic effects similar to those of cBTKi. Profiling across a panel ofBTK mutants demonstrated that docirbrutinib is effective against both wild-type and multiple resistantBTK variants, including the kinase-dead L528W mutant. In combination with venetoclax, docirbrutinibinduced significant cell death in BTK-mutant OCI-Ly10 cells and primary CLL."

Clinical • IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma

Docirbrutinib (AS-1763), a novel non-COVALENT pan-mutant BTK inhibitor, demonstrates durable clinical responses in patients with previously treated B-cell malignancies: Data from an ongoing Phase 1b study (ASH 2025) - P1 | "The study includes 3+3 dose escalation and dose expansion parts.The dose expansion part consists of three cohorts; CLL/SLL pts are allocated to Cohort 1 and NHL pts toCohort 2, both aimed at determining the recommended Phase 2 dose (RP2D), and CLL/mantle celllymphoma (MCL) pts previously treated with a ncBTKi, pirtobrutinib, to Cohort 3 for exploratory efficacyevaluation. In the ongoing Phase 1b study, docirbrutinib demonstrated encouraging anti-tumor activity with afavorable safety profile and durable responses in CLL pts heavily treated with prior therapies includingcBTKi and venetoclax and promising responses in MCL and WM pts. Updated data will be presented atthe annual meeting."

Clinical • P1 data • Atrial Fibrillation • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • TP53

Impact of Docirbrutinib (AS-1763) Treatment in CLL: Preclinical Data and Early Clinical Biomarkers (ASH 2024) - P1 | "Biological and biochemical effects were tested in treatment-naïve (TN with BTK-wild type) and relapsed/refractory (R/R with BTK and/or Bcl-2 mutant) CLL cells during in vitro investigations with 0.01, 0.1, and 1 µM docirbrutinib alone or with Bcl-2i (venetoclax) or Mcl-1i (AZD5991)...In TN CLL lymphocytes from 11 CLL pts, 72-hr incubation with docirbrutinib induced modest yet significant apoptosis which was comparable to ibrutinib or pirtobrutinib...In the dose-escalation trial, docirbrutinib treatment showed decreased BCR pathway biomarkers such as CCL3/CCL4 and phospho-BTK and PLCγ2. Updated data will be presented."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CCL3 • CD86 • CXCL12 • PLCG2

Preliminary Results from a Phase 1b Study of Non-Covalent Pan-Mutant BTK Inhibitor Docirbrutinib (AS-1763) in Patients with Previously Treated B-Cell Malignancies (ASH 2024) - P1 | "A non-covalent BTKi (ncBTKi), pirtobrutinib, was recently approved for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) after at least 2 lines of systemic therapies including cBTKis, but acquired resistance via BTK T474I and L528W mutations has been reported...Median lines of prior therapies were 4 (range, 2-5), including chemotherapy + anti-CD20 antibody (all pts [100%]), cBTKi (9/9 CLL [100%], 1/2 FL [50%]), and venetoclax (6/9 CLL [67%])...We plan to move forward to the expansion part to determine recommended phase 2 dose. Updated data will be presented at the annual meeting."

Clinical • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Oncology • TP53

PRELIMINARY RESULTS FROM A PHASE 1B STUDY OF NON-COVALENT PAN-MUTANT BTK INHIBITOR DOCIRBRUTINIB (AS-1763) IN PATIENTS WITH PREVIOUSLY TREATED B-CELL MALIGNANCIES (EHA 2025) - P1 | "A non-covalent BTKi (ncBTKi), pirtobrutinib, was recently approved for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL), but resistant BTK mutations T474I and L528W have been reported.Docirbrutinib (AS-1763) is a highly selective, pan-mutant ncBTKi which inhibits both wild-type and various c/ncBTKi-resistant mutations including C481x, T474x and L528x with IC50 values of <10 nM (Kawahata et al. Emerging clinical data from the ongoing study demonstrate that docirbrutinib has a favorable safety profile and exerts robust and durable responses in heavily pretreated pts with CLL and MCL, including those with prior BTKi and venetoclax treatment. Updated data will be presented at the annual meeting."

Clinical • P1 data • Atrial Fibrillation • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • TP53

PRELIMINARY SAFETY AND EFFICACY RESULTS FROM A PHASE 1B STUDY OF ORAL NON-COVALENT BTK INHIBITOR AS-1763 IN PATIENTS WITH PREVIOUSLY TREATED B-CELL MALIGNANCIES (EHA 2024) - P1 | "A non-covalent BTKi (ncBTKi), pirtobrutinib, was recently approved for chronic lymphocyticleukemia (CLL) and mantle cell lymphoma after at least 2 lines of systemic therapies including cBTKis, butacquired resistance via BTK T474I and L528W has been reported...Median lines of prior therapies were 4 (range, 2-5), including chemotherapy + anti-CD20 antibody (n=9; 7CLL, 2 FL), cBTKi (n=8; 7 CLL, 1 FL), and venetoclax (n=4; 4 CLL)...3 pts (2 CLLand 1 FL) at 300 mg BID are awaiting the initial radiologic assessment, but 1 pt with CLL with prior ibrutinib andvenetoclax has already shown >50% decrease in lymphocyte count in Cycle 1... Preliminary data from the ongoing study of AS-1763 indicate a favorable safety profile and clinical responsesin heavily pretreated patients with B-cell malignancies, including those with acquired resistance to cBTKis. Updated data will be presented at the meeting."

Clinical • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Oncology

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Carna Biosciences, Inc. | Phase classification: P1b ➔ P1

Phase classification • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • PLCG2

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1b | N=110 | Recruiting | Sponsor: Carna Biosciences, Inc. | Trial completion date: Jan 2028 ➔ Sep 2027 | Initiation date: May 2023 ➔ Aug 2023 | Trial primary completion date: Jan 2026 ➔ Sep 2027

Trial completion date • Trial initiation date • Trial primary completion date • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

Carna Bioscience Announces Initiation of BTK Inhibitor AS-1763 Phase 1b Study (U.S.) [Google translation] (Nikkei) - "We are pleased to announce that we have started a Phase 1b trial in the United States for the next-generation BTK inhibitor AS-1763, which we are developing for blood cancer."

Trial status • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1b | N=110 | Recruiting | Sponsor: Carna Biosciences, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

A Study of BN102 in Patients With Previously Treated CLL/SLL and B-cell NHL (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: BioNova Pharmaceuticals (Shanghai) LTD. | N=174 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1b | N=110 | Not yet recruiting | Sponsor: Carna Biosciences, Inc. | Initiation date: Dec 2022 ➔ Mar 2023

Trial initiation date • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1b | N=110 | Not yet recruiting | Sponsor: Carna Biosciences, Inc.

New P1 trial • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

A Study of BN102 in Patients With Previously Treated CLL/SLL and B-cell NHL (clinicaltrials.gov) - P1/2 | N=174 | Not yet recruiting | Sponsor: BioNova Pharmaceuticals (Shanghai) LTD.

New P1/2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Safety, pharmacokinetics, and pharmacodynamics of AS-1763, a highly selective, orally bioavailable, non-covalent BTK inhibitor, in healthy volunteers (AACR 2022) - "Background: Covalent Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib are approved for treating patients with B-cell malignancies, but their long-term efficacy is limited due to their toxicity (i.e., on-target and off-target inhibition of kinases) and acquired resistance (i.e., BTK C481 mutation). Single doses of AS-1763 up to 600 mg were well-tolerated and showed encouraging pharmacodynamics (inhibition of CD69 upregulation) with a favorable safety profile. The data support continued development of AS-1763 for patients with B-cell malignancies."

Clinical • PK/PD data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD69

AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK (AACR 2022) - "The preclinical data support the clinical development of AS-1763 in patients with B-cell malignancies both having WT and C481S mutation in BTK. The first-in-human Phase 1 clinical trial of AS-1763 in healthy volunteers (EudraCT 2020-005599-37) is currently ongoing, and the Phase 1b study in patients is expected to begin in 2022."

Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase. (PubMed, J Med Chem) - "Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials."

Journal • Hematological Malignancies • Oncology